Regulation of cerebral blood flow by intrinsic neuromodulation in wakefulness and sleep

The National Institute of Neurological Disorders and Stroke awarded the Trustees of Boston University $170,132 under Project Grant F31NS145737 on December 1, 2025, to support research on the regulation of cerebral blood flow by intrinsic neuromodulation across wakefulness and sleep states. The award is made under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853).

The research will examine neurovascular coupling through two coordinated aims. Aim 1 uses widefield imaging of the dorsal cortical surface to simultaneously measure neural calcium activity, release of neuromodulatory neurotransmitters (acetylcholine, norepinephrine, dopamine, and serotonin), and hemoglobin fluctuations across brain states; these optical measures combined with EMG and ECoG recordings will formalize the dependence of hemodynamics on neuromodulatory neurotransmitters as impulse response functions used in fMRI studies. Aim 2 measures single cortical arteriole dilation and hemodynamic fluctuations across brain states using two-photon microscopy while blocking specific neuromodulatory receptors or release through pharmacological tools and opto/chemogenetics to establish causal relationships between neuromodulator release and hemodynamic responses.

Work is performed in Boston, Massachusetts. The period of performance runs from December 1, 2025 through August 31, 2028.

Abstract

Noninvasive functional imaging techniques, such as functional magnetic resonance imaging (fmri), have a potential for diagnosing neurological diseases and evaluation of treatments. However, to fully realize this potential, we need better understanding of the process known as neurovascular coupling (NVC). My recent study in mice revealed that, during resting state, hemodynamic fluctuations depend on norepinephrine (NE), an intrinsic vasoactive neuromodulator. Using my experimental measurements, i derived a simple model that predicted hemodynamics across the cerebral cortex with high accuracy given a measure of NE and local circuit activity. The proposed study aims to extend these results to other brain states and neuromodulatory neurotransmitters. In aim 1, i will use widefield imaging of the entire dorsal cortical surface to image neural calcium activity, release of a neuromodulator (ACH, NE, DA, or 5-HT), and fluctuations in OXY/deoxy/total hemoglobin. These optical measures, together with EMG and μecog recordings, will be used to label brain state, which will be used to relate fluctuations in neuromodulator release to brain state-specific hemodynamics. Then, for each brain state, i will identify and formalize the dependence of hemodynamics on the relevant neuromodulatory neurotransmitters in terms of the impulse response function (IRF) used in fmri studies. My aim 2 is a mechanistic counterpart of aim 1. In aim 2, i will evaluate the causal relationship between the release of a specific neuromodulator and hemodynamic fluctuations across brain states. To this end, i will use two-photon microscopy to measure dilation of single cortical arterioles simultaneously with neural calcium activity and neuromodulator release. I will use pharmacological tools and opto/chemogenetics to block the receptors or neuromodulatory release while simultaneously tracking brain state transitions. The results of this project will (a) deliver new mechanistic knowledge about the regulation of cerebral blood flow by neuromodulation, across brain states, and (b) inform the choice of IRF in fmri studies. Beyond the current scope, these results would allow asking the question of whether release of specific neuromodulators can be predicted from noninvasive hemodynamic signals, something that i am interested to explore during my future postdoctoral training. For my long-term career, i intend to apply engineering principles to neuroscience questions and combine mechanistic animal studies with computational modeling, as a leader of a research group in an academic institution. The goal of my training plan is to (1) expand my scientific knowledge base in neurophotonics and computational neuroscience, (2) develop novel concepts about specific mechanisms that govern neurovascular coupling and generation of hemodynamic signals, (3) present my results at international forums and produce high-profile publications, and (4) expand a network of colleagues and collaborators.